Vascular calcification is associated with a range of diseases, and can be broadly separated into three distinct types, namely (1) intimal atherosclerotic calcification, which is calcification of the tunica intima, and includes atherosclerosis and the associated inflammation; (2) valvular calcific aortic stenosis, which is calcification of the aortic valve; and (3) arterial medial calcification, which is calcification of the tunica media, see Demer and Tintut “Vascular Calcification”, Circulation, 2008; 117, 2938-2948.
The tunica media is the middle layer of an artery or vein and is made up of smooth muscle cells and elastic tissue.
As shown in FIG. 28A, atherosclerotic calcification is eccentric and leads to lumen deformation. The deformation of the lumen is caused by a lipoprotein deposition 3, due to cholesterol-laden white blood cells (foam cells), covered by a fibrous intimal cap 4. Calcification 1 occurs throughout the atherosclerotic lesion, including in the cap 4, and focal elastinolysis 2 occurs in the tunica media adjacent to the lipoprotein deposition 3. Vessel stiffening is caused by atherosclerotic calcification.
Conversely, as shown in FIG. 28B, medial calcification is concentric. Accordingly, calcification 1 and elastinolysis occurs throughout the tunica media. Vessel stiffening is also caused by medial calcification.
At the molecular level, calcification is the formation and binding of mineral particles into the extracellular matrix. Work over the last 20 years has demonstrated that vascular calcification is a cell-mediated process with similarities to developmental osteo\chondrogenesis. Calcification results in stiffening of the matrix, which is essential for bone, but with detrimental consequences for the mechanical properties of vascular tissue.
Mönckeberg's arteriosclerosis, otherwise known as medial calcific sclerosis, is the most common variety of medial calcification. Furthermore, calcific uremic arteriolopathy (CUA), otherwise known as calciphylaxis, is a severely morbid and life-threatening form of medial vascular calcification that leads to cutaneous necrosis and panniculitis.
The reduced aortic and arterial elastance, caused by vascular calcification, impairs cardiovascular hemodynamics. This can result in hypertension, aortic stenosis, cardiac hypertrophy, myocardial and lower-limb ischemia and congestive heart failure. In particular, vascular calcification is a leading risk factor for cardiovascular disease.
Vascular calcification is also commonly associated with diabetes mellitus I, diabetes mellitus II, chronic renal disease, ageing, hyperparathyroidism, vitamin D disorders, vitamin K deficiency, osteoporosis, Kawasaki disease, arterial calcification due to deficiency of CD73 (ACDC), generalized arterial calcification of infancy (GACI), idiopathic basal ganglia calcification (IBGC), pseudoxanthoma elasticum (PXE), rheumatoid arthritis, Singleton-Merten syndrome, β-thalassemia and warfarin use.
Accordingly, there is a need for compounds which can be used to treat, prevent or ameliorate diseases associated with excessive and/or inappropriate vascular calcification, and in particular medial vascular calcification or intimal atherosclerotic calcification.